KR20170106485A - Prevention or treatment of uric acid or gout disease - Google Patents

Abstract

R₁은 수소, C_1-4 알킬 등을 나타낸다. R₂는 C_1-10 알킬 등을 나타낸다. R₃은 할로겐 등을 나타낸다.The present invention relates to a compound of formula (I), a pharmaceutically acceptable salt, solvate thereof, or a mixture thereof, for reducing uric acid levels, preventing or treating inflammation, preventing or treating uric acid or gout diseases ≪ / RTI > In particular, the present invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate thereof, for the manufacture of a medicament for the treatment or prevention of hyperuricemia, gout, gout, inflammation, pain and uric acid nephropathy To the use of a pharmaceutical composition comprising the same.

R ₁ represents hydrogen, C _1-4 alkyl or the like. R ₂ represents C _1-10 alkyl or the like. R ₃ represents halogen or the like.

Description

Prevention or treatment of uric acid or gout disease

The present invention relates to the prophylaxis or treatment of uratic or gout diseases, and more particularly to a compound or composition for the treatment or prevention of uric acid or gout diseases. The present invention also relates to a method for the treatment or prevention of uric acid or gout diseases as well as to the use of such compounds or compositions for reducing uric acid levels in a patient in need thereof and for preventing or reducing inflammation, ≪ RTI ID = 0.0 > and / or < / RTI >

High uric acid, or hyperuricemia, is a metabolic disorder caused by an increased level of uric acid caused by metabolic disturbance of substances in the body called purines. The production and excretion of uric acid in vivo is approximately the same. Regarding the amount produced, 1/3 is derived from food and 2/3 is self-synthesized in vivo. Regarding the excretion route, 1/3 is excreted by the intestines and 2/3 is excreted in the kidneys. The value of uric acid will increase if any of the above pathways is wrong. Increase in the uric acid level prevents uric acid excretion in the blood and uric acid can not be released. If the uric acid level is too high, other diseases such as gout, nephropathy and cardiovascular disease can occur.

High levels of uric acid will cause gout. Gout is a type of recurrent arthritis caused by an increase in blood uric acid levels due to metabolic disturbance of purines in the body. Elevated levels of uric acid can also cause gouty nephropathy, a renal injury caused by hyperuricemia due to excessive production of blood uric acid without proper excretion. Patients with severe hyperuricemia can cause kidney failure. Gout is a group of heterogeneous conditions with tissue damage caused by an increase in blood uric acid. This is caused by reduced metabolism of purines and / or excretion of uric acid in vivo and is indicative of symptoms of hyperuricemia. The serum uric acid content of healthy persons is 20-60 mg / L. Above 80 mg / L, urate crystals accumulate in areas of the body, such as joints, soft tissues and kidneys, leading to coronary artery disease, cholelithiasis and kidney disease, or "gout". During acute onset, urate microcrystals accumulate in the joints and cause local granulocytes in the filtration and inflammatory response. At recurrence, joint anomalies occur with a formed "ventilated nodule". Gout was a common disease in Western countries and Japan for a long time. In recent years, gout has become an epidemic in China (especially in the rib area).

Previous studies have shown that acute expression of gout is an acute inflammation process induced by urate crystallization, which begins with the interaction between the urate crystals and the resident mononuclear cells / macrophages. Finally, a number of fundamental mechanisms In most patients, the occurrence of gout is related to the rate of change (increase or decrease) in blood uric acid levels, but not to the level of blood uric acid stability. Sudden changes in blood uric acid levels cause changes in the volume or shape of the crystals so that the crystals can move within a tissue matrix that promotes the release of urate crystals from the body part where the formed gout nodules are deposited. It is a locally newly formed crystal that causes released microcrystals or chlorine reactions.

The interaction between mononuclear cells / macrophages and urate crystals is a key step in initiating the onset of acute gout. The interaction between the urate crystals and the resident macrophages causes an inflammatory response and induces the filtration of neutrophil granulocytes and mononuclear cells to improve the inflammatory response. The onset of acute gout includes a number of inflammatory factors, including predominantly chemokines such as IL-l [beta], IL-6, IL-18, TNF-a and IL-8 (CXCL-8). By determining the levels of inflammatory and anti-inflammatory factors in the joint fluid of the patient at different stages of acute gout, inflammatory factors such as IL-1β, IL-6 and TNF-α and leukocyte levels in the joint fluid And there was a significant increase.

Currently, IL-1, also known as a lymphocyte stimulator, is produced primarily by activated monocyte-macrophages. IL-1 has two different molecular forms, IL-l [alpha] and IL-l [beta]. IL-l [alpha] and IL-l [beta] synergistically stimulate the activation of antigen presenting cells and T cells and promote immune regulation by promoting B cell proliferation and antibody secretion at low local concentrations. The IL-1? Precursor is produced in immune cells such as monocytes-macrophages and dendritic cells and is converted to caspase-1-activated IL-1? In the NALP3 inflammatory complex. Activated IL-1 [beta] is released to mediate the chlorination reaction. IL-1 [beta] may cause release of IL-6 and IL-8 and may mediate filtration of neutrophil granulocytes. In addition, prompt clinical responses to IL-1 inhibitors in acute pain patients also demonstrate an important role for this factor in gout inflammation. Recent studies have shown that interleukin 1β (IL1β) plays an important role in inflammatory processes caused by the accumulation of sodium urate (MSU) crystals in gout patients (Ann Rheum Dis 2009; 68: 1613-1617).

TNF-α (tumor necrosis factor) is a polypeptide-type cytokine produced by monocytes and macrophages and plays an important role in inflammatory responses, development of the immune system, programmed cell death and lipid metabolism. TNF-a is involved in the progression of a variety of diseases including asthma, Crohn's disease, rheumatoid arthritis, neuropathic pain, obesity, type 2 diabetes, autoimmune diseases and tumors. In the immune response, TNF-α is a multifunctional modulator and acts as a powerful exothermic substance that stimulates neutrophil granulocytes, changes the behavior of vascular endothelial cells, and regulates the metabolism of some tissues.

IFN-γ (interferon γ) is a glycoprotein produced by T cells and natural killer cells in the immune system, which activates macrophages to increase the level of proinflammatory cytokines and lower the level of anti-inflammatory cytokines, Thereby improving tumor activity.

A common physical symptom of gout patients is the pathologic increase in uric acid concentration in the blood. Not everyone with increased uric acid levels will suffer from gout, but the uric acid level in each gout patient increases. The uric acid concentration increases for two reasons. The first is the reduction of urinary excretion of uric acid, and the second is the enhancement of the biosynthesis of uric acid due to dysregulation.

The ventilation is divided into a first ventilation and a second ventilation. The former is often caused by an enzyme deficiency associated with hypertension, diabetes, hyperlipidemia, obesity, metabolic syndrome and coronary heart disease and may be transmitted to his / her offspring. The latter is caused by nephropathy, blood diseases, drugs and other causes.

If the gout is not actively prevented or properly treated, the gout becomes worse and more frequent with more joint attacks, leading to a heterogeneous disease based on gout. The urate crystals accumulate in the joints and cause acute arthritis. At the same time, because the joints are attacked, gout develops into long-term arthritis. Repeated outbreaks can cause permanent damage to the joints, including long-term pain and rigidity, limited mobility, and joint deformities. As the condition progresses, the crystals accumulate in the soft tissues and form a mass called subcutaneous "ventilated nodule". Accumulation of crystals in the kidney can lead to kidney lesions leading to acute uric acid neuropathy and chronic uric acid neuropathy, which causes severe kidney damage and urinary stones in the urinary tract.

Gouty arthritis has a high incidence and is difficult to treat and recurrent. The patient experiences a lot of pain due to complications. The disease was selected by the World Health Organization as one of the top ten illnesses of the 21st century.

Until now, many epidemiologic studies have confirmed that high uric acid in the blood is an independent risk factor for hypertension. Increase in blood uric acid by 1 mg / dL increases the relative risk of hypertension by 25%. Long - term hyperlipidemia can impair pancreatic beta cell function and induce diabetes, and studies have shown that chronic hyperuricemia, as well as the onset of diabetes and a causal relationship with impaired glucose tolerance. Uric acid levels are an independent risk factor for death from coronary artery disease. Studies have shown that uric acid is an independent risk factor for death from coronary artery disease, regardless of gender. If the blood uric acid is increased by 1 mg / dL, the risk of death increases by 48% and 126% in men and women, respectively. Serum uric acid levels above 6 mg / dL are independent risk factors for coronary heart disease. A blood uric acid content of> 7 mg / dL is an independent risk factor for stroke.

Uric acid levels and kidney disease are closely related. In addition, many epidemiologic studies and animal studies have shown that uric acid directly causes microvascular lesions in the afferent arterioles, resulting in chronic inflammation of the renal arteries and chronic inflammation in the epilepsy induced by accumulation of urate crystals, It is said that it can cause kidney disease.

At present, anti-gout agents are of a limited type. Clinical treatments for gout include, but are not limited to, colchicine, uric acid synthesis inhibitors (allopurinol, bevacostat), uric acid excretion promoters (eg, probenecid, sulfinpyrazone, benzbromarone, Anti-inflammatory agents and hormones. In acute cases, colchicine, nonsteroidal anti-inflammatory drugs and hormones are used. When the condition is alleviated, uric acid synthesis inhibitor and uric acid excretion promoter are mainly used. However, these preparations have poor efficacy and side effects, which are not very helpful for treatment.

In 2012, the first-line uricase-lowering agents recommended in the American College of Rheumatology (ACR) in the Guide to Gout Therapy were allopurinol and bevacostat, which was first recommended as a first-line choice . Probenecid is provided as a first choice agent to promote uric acid excretion during uric acid-lowering therapy only when the patient is unable to take at least one xanthine oxidase inhibitor. The ACR guidelines also recommended that patients begin to receive uric acid-lowering therapy immediately after effective anti-inflammatory therapy has begun. Thus, there remains a need for new agents for the treatment or prevention of uric acid or gout diseases.

WO2005077950 discloses compounds of formula (I) of the present invention for the treatment of diseases such as lipidemia, type II diabetes and the like by activating HM74A (also known as GPR109A). However, this patent does not disclose or suggest that this compound may be useful for the prevention or treatment of uric acid or gout diseases.

WO2011057110 discloses that a xanthine derivative activates HM74A to prevent or treat diseases such as brain ischemia.

US20130150383 discloses the use of xanthine compounds for the treatment of psoriasis.

US2015080418 A1 discloses the use of xanthine compounds for the treatment of neurological disorders.

WO 9316699 A1 discloses the use of xanthine compounds for the treatment of fungal infections.

WO 9920280 A1 discloses the use of xanthine compounds for the treatment of skin itching.

EP0389282 A2 discloses the effect of xanthine compounds on brain metabolism, neuroprotection and vascular abnormalities.

Ther. Patents 2009, 19 (7), 957-967) discloses that xanthine derivatives activate GPR109A for the treatment of dyslipidemia, type II diabetes and some other diseases.

One publication (Curr Atheroscler Rep 2013, 15: 325, 1-10) discloses that GPR109A has a pharmacological effect mediating vascular inflammation.

One publication (PLoS One. 2014 Oct 17; 9 (10): e109818) indicates that GPR109A is effective in the treatment of Parkinson's disease.

None of these references, however, have reported the use of xanthine compounds in reducing uric acid levels, preventing or treating gout.

It is an object of the present invention to provide a novel method for reducing uric acid levels, preventing or reducing inflammation, and treating or preventing hyperuricemia, gout, gout inflammation, pain and uric acid nephropathy.

In order to achieve the above object, the present inventors have intensively studied. As a result, it has surprisingly been found that the kinds of xanthine compounds can reduce the uric acid levels and prevent or reduce inflammation to effectively prevent or treat hyperuricemia, gout, gout inflammation, pain and uric acid nephropathy.

Specifically, the present invention relates to the following technical solutions.

(1) Compounds of formula (I) for the reduction of uric acid levels and the prevention or reduction of inflammation in the manufacture of medicaments for the treatment and / or prevention of hyperuricemia, gout, gouty inflammation, pain and uric acid nephropathy, Acceptable salts, solvates thereof, or pharmaceutical compositions comprising them,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(2) In the use according to (1) above,

Wherein R < ₁ > represents hydrogen or methyl,

R ₂ represents ethyl, cyclopropylethyl, cyclopropylmethyl, propyl, 2-methylpropyl, butyl, 3-methylbutyl or pentyl,

R ₃ represents fluorine or chlorine.

(3) In the use according to the above (1), the compound is selected from the group consisting of:

8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

8-chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-2,6-

8-Chloro-l-methyl-3- (2-cyclopropylethyl) -3,7-dihydro-lH-purine-2,6-dione.

(4) To reduce uric acid levels,

8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

Methyl-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione, a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition comprising.

(5) for preventing or reducing inflammation,

8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

Methyl-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione, a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition comprising.

(6) In the manufacture of a medicament for the treatment and / or prevention of hyperuricemia,

8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

Methyl-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione, a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition comprising.

(7) In the preparation of a medicament for the treatment and / or prevention of gout, 8-chloro-3-pentyl-3,7-dihydro-1H-purine-

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

Methyl-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione, a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition comprising.

(8) In the manufacture of a medicament for the treatment and / or prevention of gout inflammation,

8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -33,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

Methyl-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione, a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition comprising.

(9) In the preparation of a medicament for the treatment and / or prevention of pain, 8-chloro-3-pentyl-3,7-dihydro-1H-purine-

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

Methyl-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione, a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition comprising.

(10) In the preparation of a medicament for the treatment and / or prevention of uric acid nephropathy, 8-chloro-3-pentyl-3,7-dihydro-1H- purine-

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

Methyl-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione, a pharmaceutically acceptable salt thereof, Use of the pharmaceutical composition comprising.

(11) In the use according to the above (1) to (10), the hyperlipidemia includes a first hyperlipidemia and a second hyperlipemia.

(12) In the use according to the above (1) to (10), the ventilation includes a first ventilation and a second ventilation.

(13) In the use according to the above (1) to (10), the gout inflammation includes acute gouty arthritis, subcutaneous gouty nodule, and chronic gouty arthritis.

(14) In the use according to the above (1) to (10), the pain includes acute pain, chronic pain, intractable pain and cancer pain.

(15) The use according to any one of (1) to (10) above, wherein the uric acid nephropathy includes acute uric acid nephropathy, chronic uric acid nephropathy and uric acid urinary incontinence.

(16) A pharmaceutical composition comprising at least one compound selected from the group consisting of a compound of formula (I), a pharmaceutically acceptable salt thereof and a solvate thereof, and at least one pharmaceutically acceptable carrier.

(17) A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the prophylaxis or treatment of uric acid or gout diseases,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(18) The compound according to the above (17), or a pharmaceutically acceptable salt or solvate thereof,

Wherein R < ₁ > represents hydrogen or methyl,

R ₂ represents ethyl, cyclopropylethyl, cyclopropylmethyl, propyl, 2-methylpropyl, butyl, 3-methylbutyl or pentyl,

R ₃ represents fluorine or chlorine.

(19) In the compound according to (17) above, or a pharmaceutically acceptable salt or solvate thereof, the compound is selected from the group consisting of:

8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Chloro-l-methyl-3- (3-methylbutyl) -3,7-dihydro-lH-purine-2,6-dione and

8-Chloro-l-methyl-3- (2-cyclopropylethyl) -3,7-dihydro-lH-purine-2,6-dione.

(20) In the compound according to any one of (17) to (19) above, or a pharmaceutically acceptable salt or solvate thereof, it is a hydrate.

(21) The compound according to any one of (17) to (19) above, or a pharmaceutically acceptable salt or solvate thereof, wherein the uric acid or gout disease is selected from the group consisting of hyperuricemia, gout, Or uric acid nephropathy.

(22) A compound according to any one of (17) to (19), or a pharmaceutical composition thereof, for reducing the risk of developing gout, hypertension, diabetes, hyperlipemia, obesity, metabolic syndrome, coronary heart disease and kidney damage Acceptable salts or solvates thereof.

(23) The compound according to (21) above, or a pharmaceutically acceptable salt or solvate thereof, wherein the hyperlipemia includes a first hyperlipidemia and a second hyperlipemia.

(24) The compound according to (21) above, or a pharmaceutically acceptable salt or solvate thereof, wherein the ventilation includes a first ventilation and a second ventilation.

(25) The compound according to (21) above, or a pharmaceutically acceptable salt or solvate thereof, wherein the gout includes inflammatory gouty arthritis, subcutaneous gouty nodule, and chronic gouty arthritis.

(26) The compound according to (21) above, or a pharmaceutically acceptable salt or solvate thereof, wherein the pain includes acute pain, chronic pain, intractable pain and cancer pain.

(27) The compound according to (21) above, or a pharmaceutically acceptable salt or solvate thereof, wherein the uric acid nephropathy includes acute uric acid nephropathy, chronic uric acid nephropathy and uric acid urinary incontinence.

(28) A compound of formula (I) for reducing uric acid levels, or a pharmaceutically acceptable salt or solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(29) A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for preventing or reducing inflammation,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(30) A pharmaceutical composition for the prevention or treatment of uric acid or gout diseases, comprising a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(31) The pharmaceutical composition according to (30), wherein the uric acid or gout disease is hyperlipidemia, gout, gout inflammation, pain or uric acid nephropathy.

(32) A pharmaceutical composition for reducing uric acid levels, said composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(33) An antiinflammatory pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(34) A method for the prevention or treatment of uric acid or gout diseases, comprising the step of administering a compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof to a mammal in need thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(35) The method according to (34) above, wherein the uric acid or gout disease includes hyperuricemia, gout, gout inflammation, pain or uric acid nephropathy.

(36) A method for reducing uric acid levels, comprising administering to a mammal in need thereof a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(37) An anti-inflammatory method comprising the step of administering to a mammal in need thereof a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,

Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;

R < ₃ > is selected from the group consisting of halogen and cyano.

(38) The composition according to any one of (30) to (33), wherein the composition further comprises one or more other uric acid-lowering agents, anti-gout agents and anti-inflammatory agents.

(39) A composition according to any one of (30) to (33) above, and information on conditions of a pharmaceutical composition suitable for treatment, information on storage of the pharmaceutical composition, administration information, The method comprising instructions comprising one or more types of information selected from the group consisting of information on the method.

The technical solution of the present invention has an antiinflammatory effect and inhibits the development and progression of inflammation in patients with high levels of uric acid and reduces the inflammatory response in patients with gout, gout, gout, and uric acid nephropathy . These technical solutions are also effective in reducing uric acid levels, thus further reducing the risk of developing gout, hypertension, diabetes, hyperlipidemia, obesity, metabolic syndrome, coronary heart disease and kidney damage, alleviating patient pain, Gout diseases can be treated or prevented.

In particular, the inflammatory response is due to elevated uric acid levels and the compounds of the present invention have unexpected effects of reducing uric acid levels. Therefore, the compound of the present invention can substantially alleviate the inflammatory reaction caused by an increase in uric acid, and thus can exhibit an anti-inflammatory effect.

The terms used herein have the following meanings.

The term "halogen" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Fluorine atom and chlorine atom are preferable.

The term "C _1-10 alkyl" denotes a straight or branched chain alkyl group having 1 to 10 carbon atoms, preferably a C _1-6 alkyl group having 1 to 6 carbon atoms. The above-mentioned "C _1-10 alkyl" means an alkyl group having _{1 to 10} carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec- 1-methylbutyl, 1, 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1, Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, heptyl, octyl, nonyl, decyl and the like.

The term "C _1-4 alkyl" means a straight or branched chain alkyl group having from one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- .

The term "C _2-6 alkenyl" refers to vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, Methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- Methyl-1-butenyl, 2-methyl-1-butenyl, Butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl- Ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, Methyl-1-pentenyl, 1-methyl-1-pentenyl, Methyl-2-pentenyl, 2-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl- Pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, Butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl- Butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-2-butenyl, 2-butenyl, Butenyl, 2,3-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, Butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, Ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl- Propyl, 1-ethyl-2-methyl-2-propenyl, 1,3-butadienyl, Means a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms and including a double bond such as dienyl, 1,4-hexadienyl, 2,4-hexadienyl, and the like. C _1-4 alkyl having a double bond may optionally be a cis- or trans-isomer.

The term "C _2-6 alkynyl" refers to ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, Methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl- 2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-2-pentynyl, Methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1, Dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, -Ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl, and the like, and includes a triple bond.

The term " 3-7 atomic cycloalkyl "refers to an alkane moiety having 3 to 7 carbon atoms with one hydrogen atom removed, including a monocyclic cycloalkyl, a fused cycloalkyl, a bridged cyclic group and a spiro- ≪ / RTI >

The term "monocyclic cycloalkyl" refers to 3- to 7-atom saturated monocyclic cycloalkyl and 3- to 7-atom partially saturated monocyclic cycloalkyl. Cycloalkyl " means < / RTI > "3- to 7-atom saturated monocyclic cycloalkyl" means a carbon ring compound in which the monocyclic ring is fully saturated, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, But are not limited to, cyclooctyl, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl and the like.

The term " 3- to 7-member partially saturated monocyclic cycloalkyl "refers to a partially saturated carbocyclic ring of a monocyclic ring, examples of which include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl, and the like. The term " cycloalkyl "

The term "conjugated cycloalkyl" means that the conjugated cycloalkyl group is formed from two or more cyclic structures having two adjacent cyclic structures that share two adjacent carbon atoms, and the 6-7 atomically saturated conjugated cyclic group and 6-7 Quot; means that the atom comprises a partially saturated conjugated circulator. Examples of 6-7 atom saturated conjugated circulators include bicyclo [3.1.0] hexyl, bicyclo [4.1.0] heptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [4.2.0] octyl, and the like.

An atomically partially saturated conjugated cycloalkyl group is a carbon ring compound in which the functional group of at least one ring in the conjugated cyclic ring is partially saturated, examples of which include bicyclo [3.1.0] hexy-2-enyl, But are not limited to, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] .

The term "mammal" is preferably a human.

The term "treatment" refers to the complete or partial relief of symptoms associated with a disorder or disease, or delay or halt the further development or progression of these symptoms.

The term "prevention" means preventing the occurrence of a disease or disorder in a patient at risk of developing the disease or disorder.

The term "uric acid disease" means a disease associated with abnormal uric acid levels in an organism, including, but not limited to, hyperuricemia or uric acid nephropathy.

The term "gout disease" means a disease associated with gout, including, but not limited to, gout, gout, or pain.

Primary hyperuricemia is divided into molecular deficiency hyperuricemia and unexplained congenital purine metabolic disorders. The congenital purine metabolism disorder is divided into the following four types:

(I) In the first type, the activity of 5-phospholibosyl-1-pyrophosphate synthase (PRPPS) is increased resulting in excessive synthesis of 5-phospholibosyl-1-pyrophosphate synthase and excessive production of uric acid. The type of this disorder is X-linked genetics.

(II) In the second type, the hypoxanthan-guanine phosphoribosyl transferase (HPRT) is partially deficient, leading to an increase in the concentration of 5-phospholibosyl-1-pyrophosphate synthase and an excessive production of uric acid . The type of this disorder is also X-linked.

(III) In the third type, there is a complete deficiency of the hypoxanthan-guanine phosphoribosyltransferase, resulting in too much uric acid due to the increased purine synthesis found in the Lesch-Nyhan syndrome. The type of this disorder is X-linked genetics.

(IV) In the fourth type, excessive uric acid is produced due to the deficiency of glucose-6-phosphatase and the increase in purine synthesis due to the elongation and the decrease in uric acid elimination, which are generally found in the type 1 glucose storage disease type. The type of this disorder belongs to the autosomal recessive inheritance.

The second hyperuricemia is due to 1) elevated blood uric acid levels due to various acute or chronic diseases such as 1) blood disease or malignancy, chronic poisoning, drug administration or high-purine diet, or 2) hyperuricemia caused by uric acid excretion disorder it means.

Gout is a crystal-related arthritis caused by the accumulation of sodium urate (MSU) and is directly associated with hyperuricemia due to purine metabolic disorder and / or reduced uric acid excretion. Gout means, in particular, acute arthritis and chronic gout nodular disease, including arthritis, gout nodular formation, chronic gouty arthritis, uric acid nephropathy and uric acid urinary incontinence, which are mainly acute. In severe cases, joint malformations and renal failure may occur.

The first gout is mostly hereditary, but clinically only 10 to 20% of patients have a family history of gout. Too much uric acid accounts for 10% of the causes of primary hyperuricemia. The main causes are enzyme deficiency at purine metabolism, deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT) and excessive activity of phosphate ribose pyrophosphate (PRPP) synthase. When urinary excretion decreases primarily in the kidney, about 90% become the first hyperuricemic. Although the underlying mechanism is unclear and it may be a multi-magnetic inherited disease, it can not be a kind of organic disease of the kidney.

Secondary ventilation is a clinical manifestation secondary to other diseases or caused by a particular medication. Myeloproliferative disorders such as leukemia, lymphoma, multiple myeloma, erythropoiesis, hemolytic anemia and cancer accelerate cell proliferation, thereby increasing nucleic acid conversion and inducing increased uric acid. Radiation therapy and chemotherapy for malignant tumors damage many cells and increase nucleic acid conversion, thereby increasing production of uric acid. Renal disease, including chronic glomerulonephritis, pyelonephritis, polycystic kidney disease, decreased glomerular filtration rate due to lead poisoning, and late hypertension may increase uric acid concentration by decreasing uric acid excretion. Agents such as thiazide diuretics, furosemide, ethambutol, pyrazinamide, low-dose aspirin and nicotinic acid compete with uric acid to inhibit the excretion of uric acid by tubular tubules, cause. Also, prolonged administration of immunosuppressive agents may also cause hyperuricemia in renal transplant patients, which may be related to the inhibitory effect of immunosuppressive agents on uric acid excretion by tubulointerstitials.

Gout inflammation is a lesion and inflammatory reaction caused by uric acid accumulation in the capsular, bursa, cartilage, bone and other tissues. The onset of gout inflammation is predominantly affected by genetic and family factors, mainly in males over 40 years of age. This inflammation usually occurs in the hallux joints of the hallux, and in other large joints, especially in the ankles and foot joints. The main symptom is sharp pain in the joints, and sudden unilateral seizures often occur. The periarticular tissues expand significantly and become hot, red and soft.

In relation to acute gouty arthritis, most patients do not have clear symptoms before the onset, and the patient feels tired, uncomfortable and stinging in the joints only. Acute gouty arthritis typically occurs at night, and patients often wake up with arthralgia. The pain gradually worsens to a peak in about 12 hours. The patient feels torn, cut with a knife or bitten by someone, which is unbearable. Affected joints and surrounding tissues are reddened, swollen, hot, and painful with limited function. In most cases, the symptoms disappear naturally after a few days or two weeks. The primary outbreak occurs primarily in a single joint, usually the first metatarsal joint. Thereafter, this location is associated with some patients. The affected joints are the back foot, heel, ankle, knee, wrist and elbow joints. The shoulder, hip and spine joints and temporomandibular joints are slightly involved. Multiple joints can be involved at the same time and arthritis appears. Some patients may have systemic symptoms such as fever, chills, headache, palpitations, and nausea, with increased leukocyte counts, increased erythrocyte sedimentation rate, and increased C-reactive protein levels.

Regarding intermittent outbreaks, gout attacks usually last from days to weeks, usually without sequelae, or disappear naturally, leaving only localized skin pigmentation, exfoliation, itching, and the like. After that, gout lasts for months, years or even 10 years until it recurs and goes into rest. The majority of patients suffer from recurrence within one year, and the onset age is getting longer. Associated joints generally develop from lower extremities to upper extremities, from smaller distal joints to larger joints. Gradually, the fingers, wrists and elbow joints are included. A small number of patients may include atypical symptoms such as bursa, tendon, and hay adjacent to the joint as well as joints of the shoulder, hip, ceiling, sternoclavicular or vertebrae. A small number of patients develop chronic arthritis after an initial outbreak and are not discontinued.

With regard to chronic gout nodules, gentle stone-like nodules, known as "tophi or gout nodules " at the onset of development, occur in gout patients. Subcutaneous gouty nodules and chronic gouty arthritis are the result of prolonged severe hyperuricemia with accumulation of large amounts of urate sodium crystals in the subcutaneous tissue, synovial membrane, cartilage, bone and soft tissues around the joints.

These sodium urate crystals are deposited in soft tissues and cause chronic inflammation and nodules due to fibrous tissue hyperplasia. Gouty nodules are most commonly found in the helix and are found in the first metatarsophalangeal joints of the hallux, commonly found in the fingers, wrists, elbows and knees. In a small number of patients, gout nodules may appear in the nasal cartilage, tongue, vocal cords, eyelids, aorta, heart valves and myocardium. Gouty nodules can penetrate into the bone from the skeleton around the joint, causing skeletal deformities. Or gouty nodules can destroy bones. These ventilated nodules may be found in synovial membranes near the joints, in the pericardium and cartilage. Ventricular nodules vary in size and are as small as sesame or as large as eggs.

Gouty nodules can form in the internal organs, can mainly form in the kidneys, sometimes in the ureters and bladder, but are rare in the liver, gallbladder, bile ducts and pancreas. Calcium citrate crystals have been reported to be found in saliva. No gouty nodules were found in the brain, spleen or lung. After emergence, the ventilated nodule gradually increases and gradually increases, so that the pressure increases and the local skin swells and becomes thin and shiny. Along with erosion by urate crystals, the integrity of the skin is destroyed and the elasticity is deteriorated. Skin abrasions, abrasions, compression, frozen or wound can cause ulcers. "Toothpaste-like" urate crystals leak from the skin ulcers. A sinus or pimple can be formed in the ulcer. Where secondary bacterial infections can cause suppurative focuses, chronic inflammatory granulomas will form in tissues around the ulcer due to stimulation of urate crystals. Self-healing of ulcers is difficult due to poor blood circulation and weak cell renewal, as well as infection and chronic granulomatosis and other reasons. Sepsis can be severe and can lead to death.

Gouty nodules are a characteristic symptom of gout. The formation of gouty nodules is associated with disease and blood uric acid levels. The longer the length of progression, the more likely it is to form ventilated nodules. The longer the duration of hyperuricemia, the higher the probability of gouty nodules being formed. On the other hand, a large number and number of gout nodules indicate that hyperuricemia is not well controlled, that is, the condition becomes severe. In some patients, this process is already very long, but the blood uric acid level remains in the normal range for a long time after treatment, and a rare gout is formed. The presence of gouty nodules and the number and size of gout nodules are intuitive indicators for the clinical judgment of severity of symptoms and suitability of treatment.

A typical site where subcutaneous gout is formed is the auricle. Subcutaneous gout nodules are also commonly seen in joints around the joint where gout occurs repeatedly and in areas such as olecranon, Achilles tendon and patella bursa. A subcutaneous gout nodule is a pale yellow neoplasm of varying sizes that lifts beneath the skin, thinens the skin, and releases white powder or paste after treating a skin ulcer that has not healed for an extended period of time.

Subcutaneous gout nodules and chronic gouty arthritis often coexist. The accumulation of large gout nodules in the joints can lead to bone destruction of the joints, fibrosis of the tissues around the joints, and secondary degenerative diseases. Clinical signs are persistent swelling and pain in the joints, and pain is pain in compression, deformity, and dysfunction. Chronic symptoms are relatively moderate, but can occur rapidly.

Uric acid neuropathy is a kidney injury caused by hyperuricemia, often referred to as gout neuropathy, caused by excessive production of blood uric acid or decreased excretion. Clinical signs may include urinary stones, proteinuria, edema, nocturia, hypertension, elevated blood uric acid levels, and renal tubular damage. This kind of disease is quite common in western countries, and in China, more patients are found in the north.

Disease does not follow obvious seasonal patterns, and is prone to develop in people who have weight problems or like carnivorous food and alcohol. The ratio of male to female patients is 9: 1 and 85% is middle-aged. If a patient is diagnosed at an early stage and receives appropriate treatment (to control hyperuricemia and protect renal function), kidney damage can be prevented. If the treatment timing is not appropriate or is not adequately provided, the disease may worsen and progress to end-stage renal failure requiring dialysis.

In relation to chronic uric acid nephropathy, urate crystals accumulate in the kidney epilepsy leading to chronic renal tubular interstitial nephritis (acute tubulointerstitial nephritis). Clinical manifestations include reduced urinary function, severe nighttime urination, low specific gravity urine production, proteinuria, leukopenia, mild hematuria and pain. In the latter period, the filtration function of the glomeruli may be impaired and the kidney function may deteriorate.

With respect to urinary stones in the urinary tract, the concentration of uric acid in the urine increases to a supersaturated state. Uric acid accumulates in the urinary tract and forms stones, which occur in more than 20% of patients with gout and possibly before gouty arthritis. Small stones look like sand and are excreted in the urine without any obvious symptoms. Large stones can block the urinary tract and cause kidney abdominal pain, hematuria, dysuria, urinary tract infections, milk secretion and sleeping neuropathy.

There are many factors that affect the formation of kidney stones, including age, sex, race, genetic factors, environmental factors, dietary habits and occupation that are associated with the formation of stones. Abnormal metabolism of the body, urinary tract obstruction, urinary tract infections, foreign bodies and drugs are common causes of stone formation. Urinary stones are known to contain 32 components, the most common being calcium oxalate. Other components of the stone are, for example, magnesium ammonium phosphate, uric acid, calcium phosphate and cystine (amino acid), and may also be a mixture of the above components. Like uric acid stones, urine is always acidic. Uric acid stones are hard, smooth, granular, yellowish or brownish red, and the metabolism of uric acid is abnormal.

In acute uric acid nephropathy, blood and uric acid uric acid levels increase rapidly. Many urate crystals accumulate in the renal tubules to collect the tubules and cause acute urinary obstruction. Clinical signs are urinary clearance, trauma, and acute renal failure. In addition, many urate crystals can be found in the urine. These are primarily secondary conditions caused by malignant tumors and radiation therapy and chemotherapy (ie, tumor dissolution syndrome).

In the case of increased blood uric acid levels, intra-articular accumulation of crystals can cause gouty arthritis and can cause joint deformation. The accumulation of crystals in the kidney can cause gouty kidney disease and uric acid stone to cause uremia. Increased blood uric acid levels may stimulate arterial walls, cause atherosclerosis, and exacerbate coronary artery disease and hypertension. Increased blood uric acid can damage pancreatic B cells and cause or exacerbate diabetes.

Hyperuricemia is the basis for the onset of gout, but not enough to cause gout. Gout occurs only when uric acid accumulates in the body tissue and causes damage. The higher the blood uric acid level, the higher the probability of gout over the next 5 years.

In the present invention, R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl, wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more halogens, cyano, CF ₃ or combinations thereof do.

More preferably, R ₁ is selected from the group consisting of hydrogen and unsubstituted C _1-4 alkyl groups. Even more preferably, R ₁ is selected from the group consisting of hydrogen, methyl and ethyl. Most preferably, R < _{1 >} is hydrogen or methyl.

R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Nyl is unsubstituted or optionally substituted with halogen, cyano, C _3-7 cycloalkyl or a combination thereof. R ₂ is more preferably C _1-6 alkyl, and still more preferably ethyl, cyclopropylethyl, cyclopropylmethyl, propyl, 2-methylpropyl, butyl, 3-methylbutyl or pentyl. R ₂ is more preferably C _3-6 alkyl, still more preferably C _4-5 alkyl, most preferably butyl or pentyl.

R < ₃ > is selected from the group consisting of halogen and cyano. R ₃ is preferably halogen, more preferably fluorine, chlorine or bromine, still more preferably fluorine or chlorine, and most preferably chlorine.

The above-described preferred embodiments are not exhaustive lists of the definitions of R ₁ , R ₂ and R ₃ in the formula (I) of the present invention, and technical solutions including some of the above definitions and the omitted preferred embodiments are all examples And are included in the scope of the invention. Also included within the scope of the invention are combinations of technical solutions with substituents of the above-mentioned definitions of R ₁ , R ₂ and R ₃ , various preferred embodiments and the various preferred embodiments omitted.

In one preferred embodiment of the invention, R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl; R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl; R < ₃ > is selected from the group consisting of halogen and cyano.

In another preferred embodiment of the present invention, R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl; R ₂ is C _1-10 alkyl; R < ₃ > is selected from the group consisting of halogen and cyano.

In another preferred embodiment of the present invention, R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl; R ₂ is C _1-6 alkyl; R ₃ is halogen.

In another preferred embodiment of the present invention, R ₁ represents hydrogen or methyl; R ₂ represents ethyl, cyclopropylethyl, cyclopropylmethyl, propyl, 2-methylpropyl, butyl, 3-methylbutyl or pentyl; R ₃ represents fluorine or chlorine.

In another preferred embodiment of the present invention, R ₁ represents hydrogen or methyl; R ₂ represents propyl, 2-methylpropyl, butyl, 3-methylbutyl or pentyl; R ₃ represents fluorine or chlorine.

In another preferred embodiment of the present invention, R ₁ represents hydrogen or methyl, R ₂ represents propyl, butyl or pentyl, and R ₃ represents chlorine.

Preferred examples of the compounds of the present invention are the following:

8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,

Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,

8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-

8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-

8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,

Methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-2,6-dione and 8-chloro- ) -3,7-dihydro-lH-purine-2,6-dione.

The pharmaceutically acceptable salts of the present compounds represented by formula (I) are, for example, salts formed with alkali metals, alkaline earth metals, ammonium, alkylammonium and the like, or salts formed with inorganic or organic acids. These salts include, for example, sodium, potassium, calcium, ammonium, aluminum, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, Stearate, succinate, ethyl succinate, lactobionate, gluconate, glucosheptate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate , Salts formed with cysteine, salts formed with N-acetylcysteine, hydrochlorides, hydrobromides, phosphates, sulfates, hydroiodoates such as lauryl sulfate, maleate, aspartate, glutamate, adipate, trihydroxymethylaminomethane salt, , Nicotinate, oxalate, picrate, thiocyanate, undecanoate, A salt formed of an acrylic acid copolymer, a salt formed of a carboxyvinyl copolymer, and the like.

The solvate of the compound represented by the formula (I) or a salt thereof may be, for example, but is not limited to, hydrate and the like. The hydrate is preferably monohydrate.

Further, among the compounds represented by the formula (I) of the present invention, if any chiral carbon is present, the present invention can be used in combination with any arbitrary chiral carbon associated with the chiral carbon, including, for example, racemates or any enantiomers ≪ / RTI > The present invention also includes all possible stereoisomers of the present invention. That is, the compounds of the present invention include all enantiomers, diastereoisomers, compounds of various forms of dissociation equilibrium, and any mixture or racemate thereof at any ratio or more therebetween.

The compounds of the present invention of formula (I) can be produced according to various known methods, that is, the method is not particularly limited. For example, the compound of formula (I) may be prepared according to the following reaction step, as described in the following reaction path diagrams, but the production method is not limited thereto.

[Reaction path diagram]

(Wherein R ₁ , R ₂ and R ₃ are defined as above, and X represents halogen.)

i) alkylation of the feedstock with allyl bromide;

ii) diazotization using sodium nitrite followed by hydrolysis to form intermediate B;

iii) halogenation of C ₈ with halosuccinimide, wherein R ₃ represents -F, -Cl, -Br, or -I;

iv) alkylation at N ³ , wherein R ₂ represents hydrogen or alkyl;

v) alkylation at N ¹ , wherein R ₁ represents an alkane group;

vi) removal of allyl;

vii) alkylation at N ³ , wherein R ₂ represents an alkane group;

viii) alkylation at N ¹ , wherein R ₁ represents an alkane group;

ix) formation of an aldehyde group at C ₈ ;

x) conversion of aldehyde to nitrile.

Particularly, as shown in the above reaction pathway, when R ₃ represents halogen, the feedstock 1 is reacted with allyl bromide at a temperature of 0 to 50 ° C, preferably 20 to 30 ° C, in the presence of DMSO, DMF, acetone, dioxane, Alkylation in acetonitrile, tetrahydrofuran or N-methylpyrrolidone, preferably DMSO gives intermediate A. Then diazotizing with sodium nitrite in a system formed with low concentrations of acid (e.g., acetic acid, hexane, or dilute sulfuric acid) and water at a temperature of 0-100 ° C, preferably 20-60 ° C, To form intermediate B. Intermediate B is halogenated with halosuccinimide in DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran or N-methylpyrrolidone at a temperature of 0-100 ° C, preferably 20-60 ° C to give intermediate C . Intermediate C is alkylated with a halohydrocarbon in the presence of a base in DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran or N-methylpyrrolidone at a temperature of 0-50 째 C, preferably 25 째 C, D, wherein the step of preparing intermediate D may precede the step of preparing intermediate C. When R < ₁ > represents alkyl, the intermediate D is reacted at a temperature of 0 to 120 DEG C, preferably 50 to 100 DEG C, in the presence of a base in DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran or N-methylpyrrolidone Lt; RTI ID = 0.0 > E < / RTI > under halohydrocarbon. Intermediate D (R ₁ represents hydrogen) or Intermediate E (R 1 represents alkyl) is reacted with an inert gas in dichloromethane, chloroform, carbon tetrachloride or acetone at a temperature of 0 to 60 ° C, preferably 20 to 30 ° C. Is added to morpholine or 1,3-dimethylbarbituric acid under protection, and the allyl is removed with or without a catalyst of palladium catalyst to give the compound of formula (I).

When R < ₃ > represents a cyano group, the intermediate B is reacted at a temperature of 0-50 DEG C, preferably 25 DEG C, with the presence of a base in DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran or N-methylpyrrolidone Lt; RTI ID = 0.0 > C < / RTI > Intermediate C 'is reacted with a halohydrocarbon in the presence of a base in DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran or N-methylpyrrolidone at a temperature of 0 to 120 캜, preferably 50 to 100 캜 Alkylation to give intermediate D '. Intermediate D 'is eliminated using LiHMDS or NaHMDS and then quenched with DMF, alcohol or water to obtain intermediate E'. Intermediate E 'is converted to intermediate F' in acetic anhydride, toluene or benzene under the action of hydroxylamine hydrochloride and pyridine. Intermediate F 'is added to morpholine or 1,3-dimethylbarbituric acid under the protection of an inert gas in dichloromethane, chloroform, carbon tetrachloride or acetone at a temperature of 0 to 60 ° C, preferably 20 to 30 ° C, Allyl is removed in the presence or absence of a catalyst of palladium catalyst to obtain a compound represented by the formula (I).

The aforementioned halosuccinimide may be chloro succinimide, bromo succinimide, iodosuccinimide, and the like. The aforementioned bases may be sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, and the like. The above-mentioned inert gas may be nitrogen, argon, or the like.

The intermediate product and the target product obtained by the above-mentioned reaction can be separated and purified by a conventional purification method generally used in organic synthesis chemistry such as filtration, extraction, washing, drying, concentration, recrystallization, . The intermediates may also be used directly in the next step without special purification.

The resulting general formula (I) compounds can form various solvates, such as acid addition salts, base addition salts and hydrates, in the conventional manner.

The various isomers can be separated by conventional methods using differences in physico-chemical properties among or among the isomers. For example, an optically pure isomer can be separated from the racemic mixture by a method in which the racemate is reacted with a common optically active acid such as tartaric acid, or by chromatography using an optically active column to form a diastereomeric salt have. In addition, mixtures of diastereoisomers can be analyzed, for example, by separate crystallization or chromatographic methods. In addition, optically active compounds may be prepared using suitable optically active starting materials.

The present invention includes a composition comprising at least one compound selected from the group consisting of a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, and a solvate thereof.

The composition may comprise one or more pharmaceutically acceptable carriers. The above-mentioned carrier may be, for example, water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, Cellulose, polyvinylpyrrolidone, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and other oils.

The present invention also encompasses a pharmaceutical composition comprising one or more of a uric acid-lowering agent, an anti-gout agent, and an anti-inflammatory agent together with any one of the aforementioned compounds or a pharmaceutically acceptable salt or solvate thereof. The uric acid-lowering agent is selected from the group consisting of an agent for reducing uric acid production and an agent for promoting uric acid excretion. Such anti-inflammatory agents include immunomodulating non-steroidal anti-inflammatory agents (NSAIDs) and glucocorticoids. The agent for reducing uric acid production is a xanthine oxidase inhibitor selected from the group consisting of allopurinol, febuxostat, and pegloticase. The formulation for promoting uric acid excretion is a uric acid anion transporter 1 (URAT1) inhibitor such as probenecid, benzbromarone, sulphinpyrazone and lesinurad. The anti-gout agent is a colchicin. Wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of non-selective non-steroidal anti-inflammatory agents and selective cyclooxygenase (COX-2) inhibitors. The non-selective nonsteroidal anti-inflammatory agent may be selected from the group consisting of aspirin, benorilate, indomethacin, osaminethacin, sulindac, diclofenac sodium, ibuprofen is selected from the group consisting of ibuprofen, fenbid, ketoprofen, naproxen and piroxicam. The selective cyclooxygenase (COX-2) inhibitor is selected from the group consisting of celecoxib, rofecoxib, parecoxib, and the like. The glucocorticoid may be selected from the group consisting of dexamethasone, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, prednisone, prednisolone, and Betamethasone. ≪ / RTI >

The pharmaceutical composition of the present invention comprising the compound represented by the formula (I) as an active ingredient or a pharmaceutically acceptable salt thereof or a solvate thereof may be in the form of, for example, tablets, capsules, granules, powders, Or may be administered parenterally, such as by intravenous injection, intramuscular injection, injectable sterile powders, injectable concentrates, suppositories, inhalants, transdermal absorbers, eye drops, and nasal drops. In addition, when the preparation of the medicament of any of the above-mentioned dosage forms is prepared by conventional methods, the active ingredient (s) can be used alone or in combination with other excipients such as excipients, binders, extenders, disintegrants, surfactants, lubricants, , Flavoring agents, flavoring agents, coating agents, diluents, and the like, in combination with other pharmaceutically acceptable carriers.

The present invention also encompasses a pharmaceutical composition comprising one or more types selected from the group consisting of the above-described composition, and instructions for administering the pharmaceutical composition, information indicating the disease state to which the pharmaceutical composition is directed, storage information of the pharmaceutical composition, To a kit comprising the information of

The dosage of the pharmaceutical composition of the present invention depends on the body weight, age, sex, and symptoms of the patient, and may be appropriately selected according to the composition administration method such as oral administration or parenteral administration. Hereinafter, the above-described contents of the present invention will be described in detail with reference to specific examples. However, this should not be construed as limiting the scope of the subject matter of the present invention to the following examples.

Example  One. cynomolgus monkey( Macaca fascicularis ) Pharmacokinetics experiments in

The following test samples were used:

The compounds A,

The compound B prepared by Preparation Example 1,

Compound C prepared by Production Example 3, and

The compound D. prepared by Preparative Example 4.

Animal experiments were performed at Peng-Li Biomedical Technology (Shanghai) Co., Ltd. and Shandong Hongli Medical Animal Experimental Research Co., Ltd.

Animals were purchased from Suzhou Xishan Zhongke Experimental Animal Co., Ltd.

Three non-soft cynomolgus monkeys were injected intravenously with a dose of 5 mg / kg of test compounds A, B and D, and intravenous injection of test compound C at a dose of 3 mg / kg, and one compound was tested at once . Blood was collected from the veins before and 1 hour, 3 hours, 6 hours, and 24 hours after administration and the plasma was isolated. Plasma was analyzed with a 4000 Q Trap LC-MS / MS instrument. The concentration of the test sample was output by AB Company Analyst 1.6.1. Parameters such as mean, standard deviation, and coefficient of variation were calculated using Microsoft Excel, so the values directly output in Analyst 1.6.1 do not need to be calculated. PK parameters were calculated using Pharsight Phoenix 6.2 software (NCA model).

The results of half-life (t _{1 / 2z} (h)) are shown in Table 1 below.

t _{1 / 2z} (h) (Mean ± SD) (n = 3) of compounds A, B, C, D administered intravenously to cynomolgus monkeys, group t _{1 / 2z} (h) Compound A 14.55 + - 6.69 Compound B 2.72 0.35 Compound C 41.49 + - 12.31 Compound D 5.90 + - 0.42

From the experimental results, it was confirmed that the half-life (t _{1 / 2z} (h)) values of intravenously injected A, B, C and D in cynomolgus monkeys were significantly different from each other. The timing for sample collection in the uric acid-degradation experiment was designed according to t _{1 / 2z} (h).

Example  2. Uric acid-degradation experiment

The following test samples were used:

The compounds A,

The compound B prepared by Preparation Example 1,

Compound C prepared by Production Example 3, and

Compound D prepared by Preparation Example 4;

The experiment was performed at Peng-Li Biomedical Technology (Shanghai) Co., Ltd.

Animals were purchased from Suzhou Xishan Zhongke Experimental Animal Co., Ltd.

The experiments were carried out by Komoriya K, Osada Y, Hasegawa M, Horiuchi time, Kondo S, Couch RC, Griffin TB. Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees. Eur J Pharmacol. 1993 Dec 21; 250 (3): 455-60.

Each compound was tested in 3 non-soft cynomolgus monkeys (1 #, 2 # and 3 #), and monkeys were injected intravenously with test samples. Blood was collected from the blood vessels before, 3 hours, 6 hours and 24 hours after administration. Blood was kept at room temperature. Serum was collected by centrifugation. Serum uric acid content was measured.

Reduction rate of serum uric acid = (average uric acid before administration - average uric acid after administration) / average uric acid content before administration * 100%.

The results are as follows. (t1 / 2z (h)) of Compound A, B, C and D administered intravenously to cynomolgus monkey, the content of uric acid in serum and the amount of uric acid before and after 3 hours and 6 hours of administration of Compound A The content of uric acid in serum, the rate of decrease of serum uric acid before and after administration of Compound B, the content of uric acid in serum, the rate of decrease of serum uric acid before and after administration of Compound C, and the rate of decrease of serum uric acid And the decrease rate of serum uric acid before and 3 hours after the administration of Compound D, respectively. Specific results are shown in Tables 2 to 9 below.

Test results of serum uric acid reduction by Compound A group Amount of serum uric acid (μmol / L) Animal number One# 2# 3 # 4# Before administration 75.9 91.9 63.7 77.2 After 3 hours of administration 61.9 57.0 59.9 59.6 After 6 hours of administration 67.6 47.6 50.4 55.2

Reduction rate of serum uric acid by Compound A group Reduction rate of serum uric acid (%) Animal number One# 2# 3 # 4# Before administration / / / / After 3 hours of administration 18.5 38.0 5.98 22.8 After 6 hours of administration 10.9 48.2 20.9 28.5

Test results of serum uric acid reduction by compound B group Amount of serum uric acid (μmol / L) Animal number One# 2# Average Before administration 83.8 57.6 70.7 After 3 hours of administration 69.1 52.3 60.7

Reduction rate of serum uric acid by compound B group Reduction rate of serum uric acid (%) Animal number One# 2# Average Before administration / / / After 3 hours of administration 17.5 9.2 14.1

Test results of serum uric acid reduction by compound C group Amount of serum uric acid (μmol / L) Animal number One# 2# 3 # Average Before administration 57.5 64.9 58.9 60.4 After 24 hours of administration 45.8 38.3 50.7 44.9

Reduction rate of serum uric acid by compound C group Reduction rate of serum uric acid (%) Animal number One# 2# 3 # Average Before administration / / / / After 24 hours of administration 20.3 41.0 13.9 25.7

Test results of serum uric acid reduction by compound D group Amount of serum uric acid (μmol / L) Animal number One# 2# Average Before administration 57.9 54.5 56.2 After 3 hours of administration 49.6 47.1 48.4

Reduction rate of serum uric acid by compound D group Reduction rate of serum uric acid (%) Animal number One# 2# Average Before administration / / / After 3 hours of administration 14.3 13.6 13.9

From the test results it was found that Compounds A, B, C and D can significantly reduce the serum uric acid levels of the test monkey compared to the values measured before dosing, indicating that compounds of formula (I) ≪ / RTI > gout inflammation and uric acid nephropathy.

Example  3. Uric acid-degradation test in monkeys with hyperuricemia

The following test samples were used:

The compound A prepared by Preparation Example 2

The solvent used in the examples, 5% glucose, was purchased from Chen Xin Pharmaceutical Co., Ltd., lot number 1312022142.

The reagent, uric acid (UA) used in the examples was purchased from Sigma-Aldrich Co., Ltd., lot number BCBM8832V.

Animal experiments were carried out at Shandong Hongli Medical Animal Experimental Research Co., Ltd.

Animals were purchased from Suzhou Xishan Zhongke Experimental Animal Co., Ltd.

The experiments were carried out by Komoriya K, Osada Y, Hasegawa M, Horiuchi time, Kondo S, Couch RC, Griffin TB. Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees. Eur J Pharmacol. 1993 Dec 21; 250 (3): 455-60.

UA was subcutaneously injected into the neck of three non-soft cynomolgus monkeys (1 #, 2 # and 3 #) of the model group. Blood was collected from the blood vessels before UA administration and after 0.5, 1, 2, 4, 6, and 24 hours of UA administration. Blood was kept at room temperature. Serum was collected by centrifugation. Serum uric acid content was measured.

Two weeks later, the test sample was intravenously injected into three non-soft cynomolgus monkeys (1 #, 2 # and 3 #) of the administration group. Blood was collected from the blood vessel before administration of the test sample and 2 hours after administration. Subsequently, UA was subcutaneously injected into the nape of the monkey and blood was collected from the blood vessels 1 hour, 2 hours, and 4 hours after UA administration. Blood was kept at room temperature. Serum was collected by centrifugation. Serum uric acid content was measured.

Reduction rate of serum uric acid in healthy monkeys administered test sample = (average uric acid content before administration - average uric acid content after 2 hours from the test sample) / average uric acid content before administration * 100%

Decrease of serum uric acid in monkeys with hyperuricemia after administration of test sample = Uric acid content after UA administration in the model group - Uric acid content after UA administration in the administration group / Uric acid content * (100%) in the model group.

The test results are as follows. With reference to the half-life (t1 / 2z 0.54 h) of the uric acid (UA) of cynomolgus monkeys in the model group and also the trend of changes in serum uric acid content, the timing of sample collection in the treatment group was determined. That is, samples were collected before administration, 2 hours after administration of test sample, 1 hour, 2 hours and 4 hours after administration of UA for measurement of serum uric acid content. The contents of serum uric acid and the decrease of serum uric acid in the model group and the administration group are shown in Tables 3-1, 3-2 and 3-3, respectively.

[Table 3-1]

Test results of serum uric acid reduction in the model group

[Table 3-2]

Test results of serum uric acid reduction in the administration group

[Table 3-3]

Reduction rate of serum uric acid in the administration group

From the test results it was found that the compound A was able to significantly reduce the content of serum uric acid in the test monkey compared to that of the model group (self-comparison), indicating that the compound of formula (I) Inflammation, and uric acid nephropathy.

Example  4. MSU - Induced ventilation Experiment on arthritis

The following test samples were used:

The compounds A,

Compound B prepared by Preparation Example 1, and

The compound C prepared by Production Example 3

The solvent used in the examples, dimethyl sulfoxide, was purchased from Sigma-Aldrich Co., Ltd., Lot number SZBD133SV.

The solvent, polyethylene glycol 15-hydroxystearate (Kolliphor HS 15) was purchased from Beijing Feng-Li-Jing-Qiu Trade Co., Ltd., Lot number 19888216 KO.

Solvent, glucose 5% was purchased from Chen Xin Pharmaceutical Co., Ltd., lot number 1312022142.

The reagent, UA, used in the examples was purchased from Sigma-Aldrich Co., Ltd., lot number BCBM8832V.

Male Wistar rats were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Hsin-Pai Lee, Shi-Ying Huang, and Yen-You Lin. Soft Coral-Derived Lemnalol Alleviates Monosodium Urate-Induced Gouty Arthritis in Rats by Inhibiting Leukocyte Infiltration and iNOS, COX-2 and c-Fos Protein Expression. Mar. Agents 2013, 11, 99-113.

MSU  Manufacture of crystals

1 gram of uric acid was weighed and placed in 200 mL of boiling water and heated. NaOH (2 mol / L) was then added until the pH reached 9. The solution was cleaned, allowed to cool to room temperature and then left overnight. The MSU was obtained by filtration, drying at 60 캜 for 24 hours, and sterilization at a high temperature of 180 캜.

Male Wistar rats were randomly divided into groups after growing for one week before the experiment. The volume of the toes of rats was measured one day before the experiment. The rats in the model group were subcutaneously injected with a dose of 5 mL / kg and the test sample was subcutaneously injected into the rats in the dose group at a dose of 5 mg / kg. Rats were anesthetized immediately after administration and 0.09 mL of MSU suspension was injected into the left ankle joint. The volume of the left toe was measured 9 hours after the MSU was injected into the ankle joint.

The test results are shown in Table 10 below.

Results of gouty arthritis experiment (5 mg / kg) group Toe volume change (mL) Suppression of Volume Change (%) Model group 0.504 / Compound A group 0.416 17.5 Compound B group 0.349 30.8 Compound C group 0.451 10.5

From the test results it was found that Compounds A, B and C significantly inhibited the increase in the toe volume of the test rats as compared to the model group, indicating that the compound of formula (I) is effective against hyperuricemia, gout, And is useful for the treatment and / or prevention of uric acid nephropathy.

Example  5. MSU - Induced ventilation Experiment on arthritis

The following test samples were used:

The compounds A,

Compound C prepared by Production Example 3, and

The compound D. prepared by Preparative Example 4.

The solvent used in the examples, dimethyl sulfoxide, was purchased from Sigma-Aldrich Co., Ltd., Lot number SZBD133SV.

The solvent used in the examples, polyethylene glycol 15-hydroxystearate (Kolliphor HS 15) was purchased from Beijing Feng-Li-Jing-Qiu Trade Co., Ltd., Lot number 19888216 KO.

The solvent used in the examples, 5% glucose, was purchased from Chen Xin Pharmaceutical Co., Ltd., lot number 1312022142.

The reagent, UA, used in the examples was purchased from Sigma-Aldrich Co., Ltd., lot number BCBM8832V.

Male Wistar rats were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Hsin-Pai Lee, Shi-Ying Huang, and Yen-You Lin. Soft Coral-Derived Lemnalol Alleviates Monosodium Urate-Induced Gouty Arthritis in Rats by Inhibiting Leukocyte Infiltration and iNOS, COX-2 and c-Fos Protein Expression. Mar. Agents 2013, 11, 99-113.

MSU  Manufacture of crystals

1 gram of uric acid was weighed and placed in 200 mL of boiling water and heated. NaOH (2 mol / L) was then added until the pH reached 9. The solution was cleaned, allowed to cool to room temperature and then left overnight. The MSU was obtained by filtration, drying at 60 캜 for 24 hours, and sterilization at a high temperature of 180 캜.

Male Wistar rats were randomly divided into groups after growing for one week before the experiment. The volume of the toes of rats was measured one day before the experiment. The rats in the model group were subcutaneously injected with a solvent at a dose of 15 mL / kg, and the test sample was subcutaneously injected at a dose of 15 mg / kg or 10 mg / kg in the rats of the administration group. Rats were anesthetized immediately after administration and 0.09 mL of MSU suspension was injected into the left ankle joint. The volume of the left toe was measured 9 hours after the MSU was injected into the ankle joint.

The test results are shown in Table 11 below.

Results of Gouty Arthritis Experiment group Toe volume change (mL) Suppression of Volume Change (%) Bearer group -0.031 / Model group 0.404 / Compound A (15 mg / kg) 0.264 34.7 Compound B (10 mg / kg) 0.261 35.4 Compound C group (15 mg / kg) 0.232 42.6

From the test results it was confirmed that Compounds A, C and D significantly inhibited the increase in the toe volume of the test rats as compared with the model group, indicating that the compound of formula (I) was effective against hyperuricemia, gout, And is useful for the treatment and / or prevention of uric acid nephropathy.

Rats with gouty arthritis were placed in a metabolic cage and the center of the left foot of each rat was stimulated with an electronic Von Frey pain threshold detector. The maximum stress value was recorded when each rat was released and its value was the pain value of the rat.

The test results are shown in Table 12 below.

Pain value group Pain Value (g) Bearer group 57.94 Model group 35.59 Compound A (15 mg / kg) 47.51 Compound B (10 mg / kg) 43.46 Compound C group (15 mg / kg) 43.10

From the test results it was found that Compounds A, C and D significantly increased the pain value of the test rats as compared to the model group, indicating that the compound of formula (I) was effective against hyperuricemia, gout, pain, And is useful for the treatment and / or prevention of uric acid nephropathy.

Example  6. MSU - induced gouty arthritis Experiment on experiment

The following test samples were used:

The compound B prepared by Preparation Example 1

The solvent used in the examples, 5% glucose, was purchased from Chen Xin Pharmaceutical Co., Ltd., lot number 1312022142.

The reagent, UA, used in the examples was purchased from Sigma-Aldrich Co., Ltd., lot number BCBM8832V.

Male Wistar rats were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Hsin-Pai Lee, Shi-Ying Huang, and Yen-You Lin. Soft Coral-Derived Lemnalol Alleviates Monosodium Urate-Induced Gouty Arthritis in Rats by Inhibiting Leukocyte Infiltration and iNOS, COX-2 and c-Fos Protein Expression. Mar. Agents 2013, 11, 99-113.

MSU  Manufacture of crystals

1 gram of uric acid was weighed and placed in 200 mL of boiling water and heated. NaOH (2 mol / L) was then added until the pH reached 9. The solution was cleaned, allowed to cool to room temperature and then left overnight. The MSU was obtained by filtration, drying at 60 캜 for 24 hours, and sterilization at a high temperature of 180 캜.

Male Wistar rats were randomly divided into groups after growing for one week before the experiment. The volume of the toes of rats was measured one day before the experiment. The rats in the model group were subcutaneously injected with a solvent at a dose of 15 mL / kg, and the test sample was injected subcutaneously at a dose of 15 mg / kg in the rats of the administration group. Rats were anesthetized immediately after administration and 0.09 mL of MSU suspension was injected into the left ankle joint. The volume of the left toe was measured 9 hours after the MSU was injected into the ankle joint.

The test results are shown in Table 13 below.

Results of gouty arthritis experiment (15 mg / kg) group Toe volume change (mL) Suppression of Volume Change (%) Bearer group 0 / Model group 0.450 / Compound B group 0.229 49.1

From the test results it was found that Compound B significantly inhibited the increase of the toe volume of the test rats as compared to the model group, indicating that the compound of formula (I) is effective against hyperuricemia, gout, gout, and uric acid nephropathy / RTI > and / or < / RTI >

Rats with gouty arthritis were placed in a metabolic cage and the center of the left foot of each rat was stimulated with an electronic Von Frey pain threshold detector. The maximum stress value was recorded when each rat was released and its value was the pain value of the rat.

The test results are shown in Table 14 below.

Pain value group Pain Value (g) Bearer group 54.6 Model group 27.5 Compound B group 37.2

From the test results it was found that Compound B significantly reduced the pain of the test rats compared to the model group, indicating that the compound of Formula (I) inhibited hyperlipidemia, gout, pain, gout inflammation, and uric acid nephropathy And / or prevention.

Example  7. LPS -cause TNF -α Experiment on emission

The following test samples were used:

Compound C prepared by Production Example 3, and

The compound D prepared by Preparation Example 4

The solvent used in the examples, dimethyl sulfoxide, was purchased from Sigma-Aldrich Co., Ltd., Lot number SZBD133SV.

The solvent used in the examples, polyethylene glycol 15-hydroxystearate (Kolliphor HS 15) was purchased from Beijing Feng-Li-Jing-Qiu Trade Co., Ltd., Lot number 19888216 KO.

The solvent used in the examples, 5% of glucose, was purchased from Chen Xin Pharmaceutical Co., Ltd., lot number 1312022142.

The reagent, Lipopolysaccharide (LPS) used in the examples is available from Sigma-Aldrich Co., Ltd., Lot number 114M4009V.

The reagent, phosphate buffered saline (PBS) used in the examples is available from Life Technologies, Lot number 15552504.

Male BALB / C mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Experiments were performed by Pascale Gaillard, Isabelle Jeanclaude-Etter, et al. Design and Synthesis of Novel Potent, Selective, and Vivo Active (Benzothiazol-2-yl) acetonitrile Inhibitors of the c-Jun N-Terminal. J. Med. Chem. 2005, 48, 4596-4607.

BALB / C mice were raised in SPF-rated animal rooms for a week and randomly divided into model and treatment groups according to body weight. Rats were subcutaneously injected with a solvent or test sample at a dose of 10 mg / kg. Rats were intraperitoneally injected with LPS at a dose of 15 mg / kg 30 minutes after the administration of solvent or test sample. Mice were anesthetized with sodium pentobarbital (45 mg / kg, ip) 1 hour after LPS administration. Blood was collected by cardiac puncture and the content of TNF-alpha (tumor necrosis factor) in plasma was measured with a Mouse TNF-alpha Elisa Ready-set-go kit.

The test results are shown in Table 15 below.

Results of LPS-induced TNF-a release experiments group The amount of TNF-a (pg / mL) control(%) Model group 1597 / Compound C group 1208 24.4 Compound D group 1124 29.6

From the test results it was found that Compounds C and D can significantly reduce the plasma TNF-alpha content of the test mice as compared to the model group, which is useful for the treatment and / or prevention of gout inflammation .

Example  8. ConA -cause IFN? Experiment on emission

The following test samples were used:

The compounds A,

Compound C prepared by Production Example 3, and

The compound D. prepared by Preparative Example 4.

The solvent used in the examples, dimethyl sulfoxide, was purchased from Sigma-Aldrich Co., Ltd., Lot number SZBD133SV.

The solvent used in the examples, polyethylene glycol 15-hydroxystearate (Kolliphor HS 15) was purchased from Beijing Feng-Li-Jing-Qiu Trade Co., Ltd., Lot number 19888216 KO.

The solvent used in the examples, 5% glucose, was purchased from Chen Xin Pharmaceutical Co., Ltd., lot number 1312022142;

Concanavalin A (ConA), a reagent used in the examples, was purchased from Sigma-Aldrich Co., Ltd., lot number SLBD7276V.

The reagent used in the examples, Dulbecco's phosphate buffered saline (DPBS), was purchased from Life Technologies, lot number 1627698.

Male C57BL / 6 mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Experiments were carried out by Dalya R. Soond1, Elisa Bjørgo, et al. PI3K p110δ regulates T cell cytokine production during primary and secondary immune responses in mice and humans. Blood.Author manuscript; available in PMC 2013 March 11; And Gabriele Sass, Sonja Heinlein, etc. CYTOKINE EXPRESSION IN THREE MOUSE MODELS OF EXPERIMENTAL HEPATITIS. CYTOKINE, Vol. 19, No. 3 (7 August), 2002: pp 115-120.

C57BL / 6 mice were raised in SPF-rated animal rooms for one week and randomly divided into model and treatment groups according to body weight. Rats were injected into the tail vein with a dose of 15 mg / kg ConA 30 minutes after subcutaneous injection of 20 mg / kg of solvent or test sample. Mice were anesthetized with pentobarbital sodium (45 mg / kg, intraperitoneal injection) 3 hours after administration of ConA, and then the blood was collected by cardiac puncture. Blood was placed in a centrifuge tube without anticoagulant and allowed to stand at room temperature. After one hour, the blood was centrifuged. Serum was extracted and stored at -80 ° C. The level of IFN gamma (gamma -interferon) in the serum was measured by the Mouse IFN gamma Elisa Ready-set-go kit.

The test results are shown in Table 16 below.

Results of the ConA-induced IFNγ release test group Amount of IFN? (Pg / mL) control(%) Model group 3281 / Compound A group 2025 38.3 Compound B group 2644 19.4 Compound C group 2108 35.5

From the test results, it was confirmed that Compounds A, C and D were able to significantly reduce the IFN gamma content in the serum of the test mice as compared with the model group, which is useful for the treatment and / or prevention of gout inflammation .

Example  9. In air sacccitis  Experiment on

The following test samples were used:

The compound A prepared by Preparation Example 2

The solvent used in the examples, Avicel RC-591, was purchased from FMC BioPolymer, lot number DN14827450.

The reagent, UA, used in the examples was purchased from Sigma-Aldrich.

Male SD rats were purchased from Shanghai Slack Experimental Animal Co., Ltd.

Experimental Method:

MSU  Preparation of suspension

One gram of uric acid was dissolved in 0.2 L of boiling water containing 6 mL of 1N NaOH. The pH value was titrated to 7.4. The solution was cooled to room temperature and allowed to stand overnight at 4 < 0 > C. The solution was then centrifuged, evaporated and dried to give MSU crystals. After sonication, needle-shaped crystals with a length of 5-25 μm were found under a microscope. 5 mg of crystals were placed in a glass flask and sterilized at high pressure. Sterile MSU crystals were added to 5 mL of sterile saline prior to injection into the bag.

Male Wistar rats were kept for one week and randomly divided into 6 groups. Animals were anesthetized and injected with 24 mL sterile air. The animals received a second injection of air four days later. On the seventh day, rats were inoculated into the rats in the group of the bearer and model group at a dose of 10 mL / kg; Rats in the dexamethasone group were intraperitoneally administered dexamethasone at a dose of 5 mg / kg; Colchicine group rats were injected with colchicine at a dose of 5 mg / kg. In the high-dose and low-dose groups of Compound A, rats were given stomachs at a dose of 100 mg / kg and 30 mg / kg, respectively.

One hour after the administration, 5 mL of saline was injected into the air bag on the back of the bearer group of rats and 5 mL of MSU crystal suspension (1 mg / mL) was injected into the air bag on the back of another group of rats. After 4 hours, the lavage fluid in the bladder fluid was collected and a portion of the wash fluid was used for cytological analysis. The remainder was centrifuged at 8000 rpm for 15 minutes and the supernatant was stored at -80 ° C for detection of cytokines IL-1β, IL-6, KC and TNFα. Test results were expressed as mean ± SEM and statistically analyzed by t-test.

The test results are shown in Tables 17 and 18 below.

Leukocyte count (mean ± SEM, n = 8) group Total cell number
(10 ⁴ / air sacs) White blood cell count (10 ⁴ / air sacs) Monocyte Lymphocyte Eosan Enucleate Neutrophil Bearer group 113.6 ± 20.9 106.2 ± 19.3 4.3 ± 1.3 0.9 ± 0.2 0 ± 0 2.1 ± 0.7 Model group 307.2 ± 74.2 ^*** 173 ± 31.3 11.1 ± 3.2 7.4 ± 2.7 0 ± 0 115.7 ± 77.2 ^** Dexamethasone 197.2 ± 22.8 ^$$ 171.0 ± 19.2 7.5 ± 1.1 4.8 ± 1.6 0 ± 0 13.8 ± 2.4 ^$ Colchic 212.9 ± 28.8 ^$ 171.7 ± 20.1 12.1 ± 2.5 7.8 ± 2.0 0 ± 0 21.3 ± 6.6 ^$ Compound A group
(30 mg / kg) 206.8 ± 42.9 ^$ 174.2 ± 35.4 8.1 ± 1.2 5.8 ± 1.2 0 ± 0 18.6 ± 6.4 ^$ Compound A group
(100 mg / kg) 176.2 ± 29.6 ^$$$ 151.4 ± 24.1 8.0 ± 1.9 4.6 ± 1.4 0 ± 0 12.2 ± 3.4 ^$

^** P < 0.01, ^*** P < 0.001 (compared to the bearer group);

^$ P <0.05, ^$$ P <0.01, ^$$$ P <0.001 (compared with model group)

Cytokine (mean + -SEM, n = 8) group IL-1? (Pg / mL) IL-6 (pg / mL) KC (pg / mL) TNF-a (pg / mL) Bearer group 44.1 ± 5.1 257.9 ± 37.3 3745.8 ± 281.8 12.0 + 1.7 Model group 98.1 ± 28.2 ^* 4287.4 ± 3362.4 ^*** 15776.3 ± 6515.9 40.5 ± 9.4 ^*** Dexamethasone 27.8 ± 3.9 ^$$$ 136.4 ± 44.2 ^$$$ 1653.5 ± 364.8 ^$$$ 6.6 ± 1.2 ^$$$ Colchic 112.6 ± 16.2 1132.0 + 281.4 9892.7 ± 2046.2 32.2 ± 5.3 Compound A group (30 mg / kg) 79.2 ± 15.6 1218.2 + 498.7 8742.1 + - 1151.3 29.7 ± 5.0 Compound A group (100 mg / kg) 88.6 ± 13.8 476.6 ± 140.6 5757.4 ± 554.5 18.7 ± 1.6 ^$$

^** P < 0.01, ^*** P < 0.001 (compared to the bearer group);

^$ P <0.05, ^$$ P <0.01, ^$$$ P <0.001 (compared with model group)

Test results indicate that dexamethasone and colchicin can significantly inhibit the increase in total cell number and neutrophil count in MSU-induced washes. Compound A can significantly inhibit the increase in the total cell number and neutrophil count of the washing solution at oral doses of 30 mg / kg and 100 mg / kg. Dexamethasone can significantly inhibit the increase of IL-1 [beta], IL-6, KC and TNF [alpha] induced by MSU. Compound A can significantly inhibit the increase of IL-6, KC and TNF [alpha] at an oral dose of 100 mg / kg. This test demonstrated that Compound A exhibited a significant anti-inflammatory effect in MSU-induced air sacs.

Example  10. URAT1  ( urate  transporter 1) to  Experiment on

The following test samples were used:

The compounds A,

Compound B prepared by Preparation Example 1, and

The compound D. prepared by Preparative Example 4.

Experimental Method:

1. The compound was made in a stock solution (5 mM) with dimethylsulfoxide (DMSO). This experiment included a total of eight concentrations. Final concentrations were respectively 5000 nM, 1250 nM, 312.5 nM, 78.1 nM, 19.5 nM, 4.9 nM, 1.2 nM and 0.3 nM.

2. Preparation of Buffer: HCl-free HBSS buffer (125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.3 mM calcium gluconate, 1.2 mM KH2PO4, 1.2 mM MgSO4, 5.6 mM glucose, 25 mM 4-hydroxyethylpiper (HEPES) (pH 7.4)); Lysis buffer (100 mM NaOH)

3. Transfected cells stably expressing hURAT1 (human urate transporter 1) were obtained by the following steps: placing human embryonic kidney cells (HEK-293T) on a cell culture plate containing complete medium Step, culturing the cells for 24 hours at 37 DEG C in 5% CO2, rinsing the cells with phosphate buffered saline (PBS) and trypsinization to produce a suspension containing single cells; Placing 8 x ¹⁰⁶ cells on a cell culture plate, transferring the transit-293 reagent (DNA complex (1.5 mL of Opti-MEM I reduced-serum medium, 15 μg of plasmid DNA, and 45 The transIT-293 reagent [DNA complex] was uniformly dispersed by gently shaking the cell culture plate, and a 5% aqueous solution containing 5% CO2, 37 &lt; 0 &gt; C for 48 hours.

4. Absorption of 14C-labeled uric acid in hURAT1 transfected cells: (1) hURAT1-transfected cells were placed in poly-D-lysine 96-well microplates at a cell density of 6 x 10 ⁴ / , Overnight at 37 ° C; (2) Cells were placed on poly-D-lysine 96-well microplate for 12 hours, then the cells were washed three times with 200 μL pre-heated HCl-free HBSS buffer per well, Lt; / RTI &gt; (3) Add 50 μL uric acid-containing [8-14C] (0.1 μCi / well) of chlorine-free HBSS buffer per well, add 5 μL of test compound per well, incubate at 37 ° C for 5 min ; (4) The culture buffer was removed and 100 μL of ice-cold, chlorine-free HBSS buffer was added to stop the absorption of uric acid [8-14C]; (5) The plate was washed three times with chlorine-free HBSS buffer and the buffer was removed from the wells; (6) 50 [mu] L of lysis buffer was added per well and the plate was shaken at 600 rpm for 10 minutes; (7) The microplate was placed in a centrifuge, centrifuged at 1000 rpm for 5 minutes, and 45 μL of the supernatant was placed in an Isopar-96 microplate; 8) 150 μL of Ultima Gold ™ XR scintillation cocktail was added per well and the plate was shaken at 600 rpm for 10 minutes; Isoplate-96 microplate was placed on a MicroBeta Trilux (PerkinElmer) to measure the ¹⁴ C radiant intensity.

5. Calculation of IC ₅₀ values

Inhibition rate (%) = (signal intensity of positive control - signal intensity of compound) / (signal intensity of positive control - signal intensity of negative control) x 100

GraphPad Prism 5.0 was used for analysis to obtain IC ₅₀ values.

The test results are shown in Table 19.

Inhibition of hURAT1 activity by compounds of the invention Test sample IC ₅₀ Compound A 2.52 Reshinurad ^* > 5 Compound B 3.02 Compound C 0.87

Lysineurad ^* , which is a compound of the formula: 2 - [[5-bromo-4- (4-cyclopropyl-1-naphthyl) -4H-1,2,4-thiazol- It is a new formulation developed by AstraZeneca, approved by the FDA in December 2015 for the treatment of gout.

In Table 19, it was confirmed that the compounds of the present invention have a remarkable inhibitory effect on hURAT1 (human urate transporter 1).

Preparation Example 1: Preparation of 8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-dione (Compound B)

(1) Preparation of 7-allyl-2-amino-1H-purin-6- (7H)

Guanosine (2000 g, 7.07 mol) and allyl bromide (1950.5 g, 16.20 mol) were dissolved in DMSO (100 mL) and stirred under nitrogen protection at room temperature for 18 hours. To the solution was added concentrated hydrochloric acid (37%, 5 L) and stirred for 1 hour. 2 L of methanol was added to the solution and the solution was neutralized with 2 N sodium hydroxide solution until the solid precipitated. The solid was filtered and the filter cake was dried in an oven to give a white solid (1210 g, 89.6% yield).

(2) Preparation of 7-allyl-1H-purine-2,6- (3H, 7H) -dione

Amino-lH-purin-6 (7H) -one (1200 g, 6.28 mol) was dissolved in acetic acid (3 L) and water (750 mL). An aqueous solution (600 mL) of sodium nitrite (1732 g, 25.1 mol) was added dropwise to the system described above. The mixture was stirred for 3 hours to allow the reaction to proceed. The solution was concentrated to one-third and left standing to precipitate solids. The solid was filtered and the filter cake was dried to give a light yellow solid (875 g, 72.8% yield).

(3) Preparation of 7-allyl-3-butyl-1H-purine-2,6- (3H, 7H)

2.05 mol), iodo-n-butane (422 g, 2.29 mol) and potassium carbonate (345 g, 2.50 mol) Was dissolved in anhydrous DMF (1.6 L). The mixture was stirred for 24 hours to allow the reaction to proceed. Ethyl acetate (2 L) and dilute hydrochloric acid (2 N, 500 mL) were added. Thereafter, extraction was performed. The organic phase was dried over rotary evaporation to give a light yellow solid (185 g, 35.9% yield).

(4) Preparation of 7-allyl-3-butyl-8-chloro-1H-purine-2,6- (3H, 7H)

(160 g, 0.645 mol) was dissolved in anhydrous DMF (800 mL) and NCS (94.7 g, 0.71 mol) was added dropwise to a solution of 7-allyl-3-butyl- Lt; / RTI &gt; The reaction mixture was stirred under nitrogen protection for 24 hours and then rotary evaporated. Ethyl acetate (200 mL) was added to recrystallize. The crystals were filtered and the filter cake was dried to give a pale yellow solid (110.2 g, yield: 60.5%).

(5) Preparation of 8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-

(565 mg, 2.0 mmol) and tetrakistriphenylphosphine palladium (104 mg, 0.09 mmol) in dry THF (20 mL) at -78 & And morpholine (775 mg, 8.9 mmol) were dissolved in 20 mL of dichloromethane. The reaction was carried out under nitrogen protection at room temperature for 12 hours. The solution was then concentrated and column chromatographed using a silica gel column (petroleum ether: ethyl acetate = 1: 1) to give a light yellow solid (80 mg, yield: 16.5%).

Molecular formula: C ₉ H ₁₁ ClN ₄ O ₂ ; Molecular Weight: 242.1; Mass spectrum (M + H): 243.0 1H -NMR (DMSO -d6, 400 MHz): 0.85 (t, 3H), 1.23-1.27 (m, 2H), 1.54-1.59 (m, 2H), 3.81 (t, 2H), 11.17 (s, 1 H), 14.25 (br s, 1 H).

Preparation Example 2: Preparation of 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (Compound A)

(1) Preparation of 7-allyl-2-amino-1H-purin-6 (7H)

Guanosine (200 g, 0.707 mol) and allyl bromide (19.51 g, 0.162 mol) were dissolved in DMSO (1000 mL). The reaction mixture was stirred under nitrogen protection at room temperature for 18 hours. Concentrated hydrochloric acid (37%, 500 mL) was added to the solution and stirred for 1 hour. Methanol (2 L) was added and neutralized with 2 N sodium hydroxide solution until the solid precipitated. The solid was filtered and the filter cake was dried in an oven to give a white solid (125 g, yield: 92.5%).

(2) Preparation of 7-allyl-1H-purine-2,6- (3H, 7H) -dione

Amino-lH-purin-6- (7H) -one (120 g, 0.628 mol) was dissolved in acetic acid (1.5 L) and water (150 mL). An aqueous solution (300 mL) of sodium nitrite (173.2 g, 2.51 mol) was added dropwise to the system. The reaction mixture was stirred for 3 hours. The reaction solution was concentrated to one-third and allowed to settle to precipitate a solid. The solid was filtered and the filter cake was dried to give a light yellow solid (85 g, 70.5% yield).

(3) Preparation of 7-allyl-8-chloro-1H-purine-2,6- (3H, 7H)

(2.10 g, 10.9 mmol) was dissolved in anhydrous DMF (12 mL) and N-chlorosuccinimide (1.60 g, 12.0 mmol) was added to a solution of 2- Was added thereto. The reaction mixture was stirred under nitrogen protection for 6 hours. The reaction system was poured into water, extracted with ethyl acetate and then rotary evaporated to give 1.20 g of a crude yellow solid as a crude extract.

(4) Preparation of 7-allyl-3-pentyl-8-chloro-1H-purine-2,6- (3H, 7H)

(3H, 7H) -dione (750 mg) and sodium carbonate (383 mg, 3.61 mmol) were dissolved in anhydrous DMF (10 mL), and iodo -n-pentane (690 mg, 3.48 mmol) was added thereto. The reaction mixture was stirred for 24 hours. The reaction system was poured into water. Ethyl acetate (100 mL) and dilute hydrochloric acid (2N, 50 mL) were added. Extraction was then carried out. The organic phase was dried over rotary evaporation to give 50 mg of pale yellow oil as a crude extract.

(5) Preparation of 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-

The target compound was prepared by the method described in step (5) of Example 1 (80 mg, yield: 4.6%).

Molecular formula: C10H13ClN4O2; Molecular weight: 256.1; Mass spectrum (M + H): 257.1 1H -NMR (DMSO -d6, 600 MHz): 0.83 (t, 3H), 1.19-1.29 (m, 4H), 1.57-1.60 (m, 2H), 3.84 (t, 2H), 11.19 (s, 1 H), 14.38 (br s, 1 H).

Production Example 3: Preparation of 8-chloro-1-methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione (Compound C)

(1) Preparation of 8-chloro-1-methyl-3-butyl-7- (2-propen-1-yl) -1H-purine-2,6- (3H, 7H)

(3H, 7H) -dione (565 mg, 2.0 mmol) and potassium carbonate (304 mg, 2.0 mmol) 2.2 mmol) was added to N, N-dimethylformamide (15 mL) followed by iodomethane (341 mg, 2.4 mmol). The reaction was carried out at 80 DEG C for 12 hours. The resulting product was dissolved in ethyl acetate and washed successively with a saturated solution of 2 N diluted hydrochloric acid and sodium chloride. The solution was dried and concentrated to give 400 mg of a brown product as a crude extract.

(2) Preparation of 8-chloro-1-methyl-3-butyl-3,7-dihydro-1H-purine-2,6-

(3H, 7H) -dione (400 mg), tetrakis (triphenylphosphine) palladium Fins palladium (104 mg, 0.09 mmol) and morpholine (775 mg, 8.9 mmol) were dissolved in 20 mL of dichloromethane. The reaction was carried out under nitrogen protection for 12 hours at room temperature. The resultant was then concentrated and column chromatography using a silica gel column (petroleum ether: ethyl acetate = 2: 1) yielded 112 mg of a light yellow solid. The yield in two steps was 23.1%.

Molecular formula: C ₁₀ H ₁₃ ClN ₄ O ₂ ; Molecular weight: 256.1; Mass spectrum (M + H): 257.0 1H -NMR (DMSO -d6, 400 MHz) 0.88 (t, 3H), 1.27-1.32 (m, 2H), 1.60-1.65 (m, 2H), 3.23 (s, 3H ), 3.92 (t, 2H), 14.45 (s, 1 H).

Production Example 4: Preparation of 8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (Compound D)

120 mg of the target compound, which had a yield of 26.3% in two steps, was prepared by the method described in Examples 1-3.

Molecular formula: C ₁₁ H ₁₅ ClN ₄ O ₂ ; Molecular Weight: 270.1; Mass spectrum (M + H): 271.1 1H -NMR (DMSO -d6, 400 MHz) 0.86 (t, 3H), 1.25-1.33 (m, 4H), 1.62-1.67 (m, 2H), 3.23 (s, 3H ), 3.92 (t, 2H), 14.45 (br. S, 1H).

Preparation Example 5: Preparation of 8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-2,6-dione (Compound E)

The target compounds were prepared by the methods described in Examples 1-3.

1H-NMR (DMSO -d6, 400 MHz) 0.90 (d, 6H), 1.47-1.62 (m, 3H), 3.86 (t, 2H), 11.18 (br.s, 1H), 14.38 (br.s, 1H ).

Preparation Example 6: Preparation of 8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-2,6-dione (Compound F)

The target compounds were prepared by the methods described in Examples 1-3.

1H, NMR (DMSO- d6 , 400 MHz) 0.00-0.06 (m, 2H), 0.36-0.42 (m, 2H), 0.67-0.77 , 2H).

Production Example 7: Preparation of 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione monohydrate

(1) Preparation of 7-allyl-2-amino-1H-purin-6 (7H)

Guanosine (4000 g, 14.1 mol) and allyl bromide (3900 g, 32.2 mol) were dissolved in DMSO (11 L). The solution was stirred at room temperature for 24 hours. Concentrated hydrochloric acid (37%, 7500 mL) was added to the solution and stirred for 1 hour. Methanol (20 L) was added to the solution and neutralized with a saturated solution of sodium hydroxide until the solid precipitated. The solid was filtered and washed with water, and the filter cake was dried in an oven to give a white solid (1585 g, yield: 58.7%).

(2) Preparation of 7-allyl-1H-purine-2,6- (3H, 7H) -dione

Amino-lH-purin-6 (7H) -one (1584 g, 8.29 mol) was dissolved in acetic acid (8.5 L) and water (1500 mL). An aqueous solution of sodium nitrite (2277 g, 33 mol) was added dropwise to the above system. The reaction mixture was stirred overnight. The solid was filtered and washed with water. The filter cake was dried to give a white solid (1086 g, yield: 68.2%).

(3) Preparation of 7-allyl-8-chloro-1H-purine-2,6- (3H, 7H)

(2166.3 g, 11.3 mmol) was dissolved in anhydrous DMF (8 L) and N-chlorosuccinimide (1657 g, 12.4 mmol) was added to a solution of 2- Was added thereto. The reaction mixture was stirred under nitrogen protection for 24 hours. EA was added and the solution was cooled and suction filtered. The solid was filtered, washed with EA and dried to give a white solid (1804 g, 70.6% yield).

(4) Preparation of 7-allyl-3-pentyl-8-chloro-1H-purine-2,6- (3H, 7H)

2,6- (3H, 7H) -dione (200 g, 0.88 mol) was dissolved in anhydrous DMF (1.2 L). After addition of sodium carbonate (116.6 g, 1.1 mol), iodo-n-pentane (173 g, 0.87 mol) was also added. The reaction mixture was stirred for 4 days. The reaction system was poured into water and the solid was precipitated. Suction filtration was performed. The resulting solid was washed with n-hexane. The solid was again filtered by suction and dried to give a white solid (197 g, yield: 75.2%).

(5) Preparation of 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione monohydrate

(3 g, 7H) -dione (96 g, 0.32 mol), tetrakistriphenylphosphine palladium (13 g, 0.32 mol) 0.011 mmol) and N, N-dimethylbarbituric acid (253 g, 1.62 mol) were dissolved in 1 L of dichloromethane. The reaction was carried out under nitrogen protection at room temperature for 12 hours, followed by suction filtration. The obtained solid was dissolved in an aqueous solution of sodium hydroxide and washed with dichloromethane. The pH of the aqueous phase was titrated to 4 with dilute HCl. Solids precipitated. Suction filtration was performed. The precipitated solid was dried to give a white solid (60 g, yield: 67.7%).

Molecular formula: C ₁₀ H ₁₅ ClN ₄ O ₃ ; Molecular Weight: 274.1; Mass spectrum (M + H): 257.1 1H -NMR (DMSO -d6, 400 MHz): 0.84-0.86 (t, 3H), 1.28 (m, 4H), 1.63 (m, 2H), 3.85 (t, 2H) , 11.22 (s, 1 H), 14.38 (br s, 1 H).

Claims (14)

A compound represented by the formula (I), or a pharmaceutically acceptable salt or solvate thereof for the prophylaxis or treatment of a uric acid disease and / or a gout disease,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,
Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more of halogen, cyano, CF ₃ or combinations thereof;
R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted by unsubstituted or one or more halogens, cyano, C _3-7 cycloalkyl or a combination thereof;
And R &lt; ₃ &gt; is selected from the group consisting of halogen and cyano, or a pharmaceutically acceptable salt or solvate thereof. The method according to claim 1,
Wherein R &lt; ₁ &gt; represents hydrogen or methyl,
R ₂ represents ethyl, cyclopropylethyl, cyclopropylmethyl, propyl, 2-methylpropyl, butyl, 3-methylbutyl or pentyl,
And R &lt; ₃ &gt; represents fluorine or chlorine, or a pharmaceutically acceptable salt or solvate thereof. The compound of claim 1, wherein said compound is selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.
8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,
8-chloro-3-butyl-3,7-dihydro-1H-purine-2,6-
Methyl-3-butyl-3,7-dihydro-1H-purine-2,6-dione,
Methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione,
8-chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-
8-chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1H-purine-
8-chloro-3- (2-methylpropyl) -3,7-dihydro-1H-purine-
8-chloro-3- (cyclopropylmethyl) -3,7-dihydro-1H-purine-2,6-dione,
8-chloro-1-methyl-3- (3-methylbutyl) -3,7-dihydro-1H-purine-2,6-
8-Chloro-l-methyl-3- (2-cyclopropylethyl) -3,7-dihydro-lH-purine-2,6-dione. 4. A compound according to any one of claims 1 to 3, wherein said compound, or a pharmaceutically acceptable salt or solvate thereof, is a hydrate (hydrate), or a pharmaceutically acceptable salt thereof Salts or solvates thereof. The compound according to any one of claims 1 to 4, wherein the uric acid or goutous disease is hyperuricemia, gout, gout inflammation, pain or uric acid nephropathy, or a pharmaceutically acceptable salt thereof. Possible salts or solvates thereof. 6. The compound of claim 5, wherein the hyperlipidemia comprises a first hyperlipidemia and a second hyperlipidemia, or a pharmaceutically acceptable salt or solvate thereof. 6. The compound of claim 5, wherein the venting comprises a first vent and a second vent, or a pharmaceutically acceptable salt or solvate thereof. 6. The compound of claim 5, wherein the gout inflammation comprises acute gouty arthritis, subcutaneous tophi, and chronic tophiarthritis, or a pharmaceutically acceptable salt or a mixture thereof. Solvate. 6. The compound according to claim 5, wherein the pain comprises acute pain, chronic pain, intractable pain and cancer pain, or a pharmaceutically acceptable salt or solvate thereof. 6. The compound according to claim 5, wherein the uric acid nephropathy comprises acute uric acid nephropathy, chronic uric acid nephropathy and uric acid urinary incontinence, or a pharmaceutically acceptable salt or solvate thereof. A compound represented by the formula (I) for reducing the uric acid level, or a pharmaceutically acceptable salt or solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl, wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more halogens, cyano, CF ₃ or combinations thereof;
R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen atom, cyano, C _3-7 cycloalkyl or a combination thereof;
And R &lt; ₃ &gt; is selected from the group consisting of halogen and cyano, or a pharmaceutically acceptable salt or solvate thereof. A compound represented by the formula (I) for preventing or reducing inflammation, or a pharmaceutically acceptable salt or solvate thereof,

Wherein R ₁ is selected from the group consisting of hydrogen and C _1-4 alkyl,
Wherein said C _1-4 alkyl is unsubstituted or optionally substituted with one or more halogens, cyano and CF ₃ or combinations thereof;
R ₂ is selected from the group consisting of C _1-10 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein said C _1-10 alkyl, C _2-6 alkenyl, or C _2-6 alk Is optionally substituted with an unsubstituted or halogen, cyano, C _3-7 cycloalkyl or a combination thereof;
And R &lt; ₃ &gt; is selected from the group consisting of halogen and cyano, or a pharmaceutically acceptable salt or solvate thereof. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof. Comprising administering to a mammal in need thereof a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment and / Prevention or treatment.